title: HIF-2α protects human hematopoietic stem/progenitors and acute myeloid leukemic cells from apoptosis induced by endoplasmic reticulum stress.
abstract: Hematopoietic stem and progenitor cells (HSPCs) are exposed to low levels of oxygen in the bone marrow niche, and hypoxia-inducible factors (HIFs) are the main regulators of cellular responses to oxygen variation. Recent studies using conditional knockout mouse models have unveiled a major role for HIF-1α in the maintenance of murine HSCs; however, the role of HIF-2α is still unclear. Here, we show that knockdown of HIF-2α, and to a much lesser extent HIF-1α, impedes the long-term repopulating ability of human CD34(+) umbilical cord blood cells. HIF-2α-deficient HSPCs display increased production of reactive oxygen species (ROS), which subsequently stimulates endoplasmic reticulum (ER) stress and triggers apoptosis by activation of the unfolded-protein-response (UPR) pathway. HIF-2α deregulation also significantly decreased engraftment ability of human acute myeloid leukemia (AML) cells. Overall, our data demonstrate a key role for HIF-2α in the maintenance of human HSPCs and in the survival of primary AML cells.
authors.affiliation: Haematopoietic Stem Cell Laboratory, London Research Institute, Cancer Research UK, WC2A 3LY, London, UK; INSERM U 1035, Bordeaux, F-33076 France; Université Bordeaux Segalen, Bordeaux, F-33076 France.
authors.forename: Kevin
authors.initials: K
authors.lastname: Rouault-Pierre
authors.forename: Lourdes
authors.initials: L
authors.lastname: Lopez-Onieva
authors.forename: Katie
authors.initials: K
authors.lastname: Foster
authors.forename: Fernando
authors.initials: F
authors.lastname: Anjos-Afonso
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lamrissi-Garcia
authors.forename: Martin
authors.initials: M
authors.lastname: Serrano-Sanchez
authors.forename: Richard
authors.initials: R
authors.lastname: Mitter
authors.forename: Zoran
authors.initials: Z
authors.lastname: Ivanovic
authors.forename: Hubert
authors.initials: H
authors.lastname: de Verneuil
authors.forename: John
authors.initials: J
authors.lastname: Gribben
authors.forename: David
authors.initials: D
authors.lastname: Taussig
authors.forename: Hamid Reza
authors.initials: HR
authors.lastname: Rezvani
authors.forename: Frédéric
authors.initials: F
authors.lastname: Mazurier
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonnet
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D017382:Reactive Oxygen Species; D000099162:Endothelial PAS Domain-Containing Protein 1